Obsessive compulsive disorder (OCD) and related neurological disorders are estimated to afflict roughly 2% of the world population. The causes for these disorders are not well understood, and as such, effective intervention strategies are lacking. Although one promising hypothesis states that activity imbalance between the direct versus indirect striatal projection pathways of the basal ganglia underlies OCD-like behaviors, there have been no direct tests of this hypothesis to date. I will investigate the role of activity imbalance in the direct versus indirect pathways of the basal ganglia in the expression of OCD-like behaviors in mice through two complementary specific aims. Specific Aim 1 will make use of the recently described SAPAP3 knockout mouse model of OCD-like behavior, which was developed in our lab (Welch et al, 2007 Nature). Although previous work demonstrated general cortico-striatal glutamatergic synaptic defects in mixed populations of striatal medium spiny neurons (MSNs), our working hypothesis is that divergent defects with potentially salient physiological impacts may occur in direct versus indirect pathway-projecting MSNs. I will perform whole-cell electrophysiology on direct and indirect pathway-projecting MSNs to test for pathway specific defects that could not previously be resolved from mixed population recordings. In Specific Aim 2 I will generate novel transgenic mouse lines to directly silence neuronal activity in the direct and/or indirect pathways in vivo. This approach will allow inducible and reversible silencing of the specific pathway of interest in awake behaving mice, and thus will provide the most direct test to date of the contribution of pathway specific activity imbalance to quantifiable OCD-like behaviors. Analysis of these animals will be carried out by combined behavioral and electrophysiological assessment. By altering the balance of activity in the direct versus indirect pathways through selective pathway silencing I expect to elucidate general mechanisms of basal ganglia circuit dysfunction that are central to the expression of OCD-like behaviors. This work promises to significantly advance our understanding of the etiology of clinically relevant forms of OCD, and further to identify novel pharmacological targets for treatment of a wide range of related neurological disorders in humans. [unreadable] [unreadable]